This invention relates to improved products and methods for remineralizing subsurface lesions in teeth and for mineralizing exposed tubules in dentin so as to prevent demineralization thereof. More particularly, this invention relates to solid dentifrice products containing cationic and anionic salts having different solubilities in water and to methods of using such products to remineralize subsurface lesions in teeth and/or to mineralize exposed tubules in dentin.
The primary component of the enamel and dentin in teeth is calcium phosphate in the form of calcium hydroxyapatite. While highly insoluble at normal oral pHs, the calcium phosphate in the teeth tends to be relatively soluble in acidic media. Consequently, carious lesions can form in the subsurface of a tooth when such tooth is exposed to acids formed from the glycolysis of sugars caused by various oral bacteria.
Because saliva is supersaturated with respect to calcium and phosphate ions, saliva helps protect teeth against demineralization and can slowly remineralize teeth which have become demineralized by acids. It is well known that the presence of fluoride ions can enhance the natural remineralization process and this is one of the accepted mechanisms by which fluoride toothpastes, and rinses protect against caries. However, the efficacy of fluoride-containing toothpastes and rinses to remineralize teeth is limited by the modest levels of calcium and phosphate in saliva. It is evident from the prior art that it is highly desirable to increase the available concentration of calcium and phosphate ions in the oral cavity to speed up the remineralization process. However, because of calcium phosphate""s low solubility at the pH of saliva, the addition of higher levels of dissolved calcium and phosphate ions is not easily accomplished.
Remineralization of dental enamel has been carried out experimentally, both in vivo and in vitro. Some studies have concentrated on the remineralizing properties.of saliva and of synthetic solutions supersaturated with respect to hydroxyapatite. Such studies comprise the subject matter of U.S. Pat. No. 3,679,360 (Rubin) and U.S. Pat. No. 4,097,935 (Jarcho).
Generally, the supersaturated solutions or slurries used in the aforementioned Rubin and Jarcho patents for remineralization experiments have been prepared from a single form of calcium phosphate. When a carious lesion is flooded with one of these supersaturated solutions, the calcium and phosphate ions in the form of precipitated hydroxyapatite remineralize the lesion. However, use of these solutions is impractical for several reasons. First, the amount of calcium and phosphate ions available for remineralization in these supersaturated solutions is too low. It is reported that it takes approximately 10,000 unit volumes of the usual supersaturated solution to produce one unit volume of mineral. Thus, remineralization by this method requires both an excessive volume of fluid and an excessive number of applications. The supersaturated solutions are inherently limited in this respect because such solutions cannot maintain their supersaturated state. When the hydroxyapatite precipitates out to the point where the solution is no longer supersaturated, new supersaturated solution must be introduced or the remineralization process stops.
Another problem with single calcium phosphate slurries is that as the hydroxyapatite precipitates out of solution, the pH of the solution changes. Unless the old solution is removed from contact with the tooth material, the solution may become too acidic or alkaline and may damage the dental tissue.
U.S. Pat. No. 4,080,440 (Digiulio et al) discloses a metastable solution of calcium and phosphate ions at a low pH (between 2.5 and 4.0) under which conditions the solubility of calcium phosphate salts is high. After penetration of the solution into demineralized enamel, remineralization results from the precipitation of calcium phosphate salts when the pH rises. Fluoride ions can be included in the metastable solution. A significant disadvantage of the use of metastable solutions is that the relatively low pH might demineralize the dental enamel and/or injure other tissue.
U.S. Pat. Nos. 4,177,258, 4,183,915 and 4,348,381 (Gaffar et al) disclose a remineralizing solution containing supersaturated concentrations of calcium ions, phosphate ions and a fluoride source stabilized by the presence of an antinucleating agent such as diamine tetramethylenephosphonic acid, ethylenediamine tetramethylenephosphonic acid and 2-phosphonobutane-tricarboxylic acid-1,2,4, or the water-soluble salts thereof. This solution is preferably adjusted to the neutral pH range where the solution is alleged to most effectively remineralize sub-surface lesions. Even though the antinucleating agent would be expected to stabilize the solution, equilibrium of the supersaturated concentrations is still found difficult to maintain and avoid precipitation of hydroxyapatite and changes in the pH of the solution. Most importantly, in order to obtain long-term (e.g., long-term) storage stability of these solutions, the concentration of calcium phosphate and, if used, fluoride is severely limited, thus limiting the remineralization potential of the formulation.
U.S. Pat. No. 4,083,955 (Grabenstetter et al) and U.S. Pat. No. 4,397,837 (Raaf et al) disclose a process for remineralizing demineralized enamel by the consecutive treatment of tooth surfaces with separate solutions containing calcium ions and phosphate ions. In this process, fluoride ions may be present in the phosphate solutions. It is immaterial which ionic solution is used to treat the teeth first. By sequentially applying calcium and phosphate ions to the tooth surface, high concentrations of the ions are able to penetrate into lesions in solution form, where the ions precipitate as a calcium phosphate salt when ions from the second treatment solution diffuse in. While apparently successful, this method involves the inconvenience of a plurality of sequential applications, which can also be time consuming.
U.S. Pat. No. 4,606,912 (Rudy et al.) teaches a method of making a clear aqueous mouthwash solution capable of remineralizing lesions in teeth by forming an aqueous solution containing a source of calcium ions and a chelating agent for calcium ions, causing the chelation of at least 50% of the calcium ions and subsequently adding a source of phosphate ions to the aqueous solution. Here too, while somewhat effective, the addition and necessary control of the amount of chelating agent makes the concept impractical.
Another problem with known remineralization techniques is that the remineralization may stop before the lesion is completely remineralized due to build-up of the remineralized tooth material in or on the outer layer of the tooth""s surface. This build-up occurs when the rate of remineralization is too fast and prevents the diffusion of the mineral into the deeper regions of the lesion, thus thwarting the full remineralization of the tooth.
U.S. Pat. Nos. 5,037,639; 5,268,167; 5,437,857; 5,427,768; and 5,460,803 (all to Tung) involve the use of amorphous calcium compounds such as amorphous calcium phosphate (ACP), amorphous calcium phosphate fluoride (ACPF) and amorphous calcium carbonate phosphate (ACCP) for use in remineralizing teeth. These amorphous compounds or solutions which form the amorphous compounds when applied either onto or into dental tissue prevent and/or repair dental weaknesses such as dental caries, exposed roots and dentin sensitivity. The compounds are claimed to have high solubilities, fast formation rates and fast conversion rates (to apatite).
Remineralization is accomplished by bringing the amorphous compound into contact with the dental tissue. This can be done directly, i.e., putting an amorphous compound directly on.the tooth, or indirectly through a carrier, i.e., incorporating the amorphous compound in a carrier such as a gel, a chewing gum, or a toothpaste and applying the carrier to the dental tissue. Once contact is established with the tooth, the amorphous calcium phosphate compounds will recrystallize to the less soluble apatite form in the lesion and reform the tooth. However, under conditions where amorphous calcium phosphate compounds are stable, the quantity of calcium and phosphate released is relatively low and, therefore, remineralization is slower than desirable.
The aforementioned patents to Tung also teach the use of two-part solutions wherein a first part contains phosphate salt(s) and a second part contains calcium salt(s), wherein either the first part or the second part further contains carbonate salt(s). In addition, the Tung patents teach solutions formed by dissolving in water a solid powder containing calcium salt(s), phosphate salt(s), and carbonate salt(s). These solutions are then applied to dental tissue. The Tung patents further teach the use of non-carbonated solid powders containing mixtures of calcium salts and phosphate salts which can be applied directly to the tooth or dispersed in gel, chewing gum, or other non-aqueous mediums such as toothpaste which is placed in contact with the tooth. The patents teach that these powders are easily dissolved in saliva and then reprecipitated as an amorphous calcium phosphate compound. However, the Tung patents do not disclose the pHs of aqueous solutions formed from the non-carbonated solid powder.
Effective remineralizing/mineralizing products and methods are continually desired which do not require the presence of carbonate salts to achieve stability, remineralization and/or mineralization. It is also continually desirable to provide remineralizing/mineralizing products and methods which directly form hydroxyapatite at the subsurface of the tooth rather than first forming an amorphous calcium phosphate as an intermediate. In addition, it is continually desirable to provide a remineralization product in the form of a one-part, stable remineralizing composition which is not negatively affected by a rise in pH or temperatures or which can efficiently remineralize teeth. Finally, there is a continual need for a method of remineralizing dental enamel which employs a stable, one-part remineralizing product which does not require excessive amounts of calcium and phosphate salts or inordinately long, frequent or sequential exposure times.
Remineralizing/mineralizing one-part and two-part products which overcome many of the aforementioned problems are disclosed in copending, commonly assigned U.S. patent application Ser. No. 08/512,473 (filed Aug. 8, 1995); Ser. No. 08/465,875 (filed Jun. 6, 1995); Ser. No. 08/512,286 (filed Aug. 8, 1995); and Ser. No. 08/512,287 (filed Aug. 8, 1995).
Application Ser. No. 08/512,473 discloses one-part and two-part products and methods of using same to remineralize subsurface lesions. The one-part and two-part products contain at least one water-soluble calcium salt, at least one water-soluble divalent metal salt wherein the divalent metal is other than calcium and at least one water-soluble phosphate salt. In the two-part products, the calcium and divalent metal salts are disposed in a first discrete component, and the phosphate salt(s) is disposed in a second discrete component. The two-part product may further contain a dispensing means for allowing the first and second components to be simultaneously dispensed from the product so as to permit the dispensed first and second components to simultaneously contact the tooth or teeth being treated. The aqueous solution formed by mixing the salts used in the one-part and two-part products has a pH of from about 4.0 to about 7.0.
Application Ser. No. 08/465,875 discloses a two-part product and method of using same for remineralizing dental enamel, wherein the product contains a first discrete component containing at least one water-soluble calcium salt and a second discrete component containing at least one water-soluble phosphate salt and at least one water-soluble fluoride salt. The product may further contain a means for allowing the first and second components to be simultaneously dispensed from the product. The first and second components of the product each have a pH such that when the two components are mixed to form an aqueous mixed solution, the solution has a the pH of from about 4.5 and 10.0.
Application Ser. No. 08/512,286 is directed to a chewing gum product and method of using same for remineralizing subsurface lesions in teeth, wherein the product contains a water-soluble cationic portion composed of at least one water-soluble calcium salt and at least one water-soluble, non-toxic divalent metal salt-wherein the divalent metal is other than calcium; a water-soluble anionic portion containing at least one water-soluble phosphate salt; and a gum base. The anionic and cationic portions are disposed in the product such that chewing of the product in the presence of water and/or saliva causes the anionic and cationic portions to be simultaneously released into the water and/or saliva so as to form a mixed aqueous solution therewith. The anionic and cationic portions each have a pH when dissolved in water and/or saliva such that the mixed aqueous solution has a pH of from about 4.0 to 7.0.
Application Ser. No. 08/512,287 is directed to one-part, non-aqueous products and methods of using same for remineralizing subsurface lesions, wherein the products contain at least one water-soluble calcium salt; at least one water-soluble phosphate salt; either a stabilizer or a hydrophilic, non-aqueous, water-soluble vehicle; and, optionally, at least one water-soluble fluoride salt. When the components are mixed with water or saliva to form an aqueous mixed solution, the solution has a pH of from about 4.5 to about 10.0.
In the one-part and two-part products disclosed in the foregoing applications, the cationic and anionic components are kept separate from one another until use of the product. In addition, the cations and anions are delivered simultaneously to the surface of the tooth being treated. These factors, along with the pH of the aqueous solution and the use in some cases of at least one water-soluble divalent metal salt, are helpful to allowing the cations and anions to have ample time to diffuse through the surface of the tooth to the subsurface before undergoing precipitation.
For mineralization or remineralization of enamel or dentin to occur, the concentration of calcium and phosphate ions in saliva must be above the concentration required to saturate the solution with respect to the formation of calcium hydroxyapatite, octacalcium phosphate, dicalcium phosphate dihydrate, or other form of insoluble calcium phosphate. At pHs above about 6.5, these requirements are met by the levels of calcium and phosphate in normal human saliva. However, because the concentration of calcium and phosphate ions in normal human saliva is only modest, even at pHs above 6.5, the rate of mineralization produced by normal saliva is very slow even when fluoride is present to catalyze the process. When the pH is above about 7, raising the concentration of calcium and phosphate ions much beyond that normally present in saliva does not, however, significantly increase remineralization. Because of the high insolubility of calcium phosphate salts above pHs of about 7, excessively rapid precipitation occurs which does not allow time for the ions to penetrate the tooth.
At pHs below about 7, significant remineralization will occur only if the concentration of calcium and phosphate ions in the saliva is above the concentration required to saturate the solution with respect to the formation of dicalcium phosphate dihydrate. Under these pH conditions, it has been demonstrated that remineralization can be accelerated by increasing the degree of supersaturation in saliva. Inasmuch as the solubility of dicalcium phosphate increases with decreasing pH, it has been found that when lesions are remineralized with solutions having a pH in the range of 4.5 to 7.0 and containing supersaturated quantities of calcium and phosphate ions, the optimum concentration of calcium ions needed to maximize the process increases with decreasing pH. Below a pH of about 4.0, dicalcium phosphate dihydrate becomes the stable precipitating species from supersaturated solutions. Under these pH conditions, it takes very high levels of calcium and phosphate to saturate the solutions. Under such conditions, there is a real danger with fairly high concentrations of calcium and phosphate that the solution will be undersaturated and demineralization of the teeth being treated will occur.
It has also been found that the simultaneous provision of very high calcium and phosphate ion concentrations can result in premature precipitation of the calcium salt before the ions can penetrate the tooth or premature precipitation so as to block the entrances of the pores in tooth enamel and dentin and thereby prevent further remineralization.
Thus, a problem apparently exists in that to control untimely precipitation, the concentration of either the dissolved calcium ions or the dissolved phosphate ions needs to be limited. This in turn would be expected to disadvantageously limit the maximum rate of mineralization or remineralization which could be accomplished.
In addition, the use of very high calcium and fluoride ion concentrations can result in premature precipitation of the fluoride ions before these ions can penetrate the tooth. As mentioned previously herein, fluoride ions can enhance the natural remineralization process. However, sufficient levels of fluoride ions are generally required to be present. Calcium cations and fluoride anions precipitate to form calcium fluoride, a salt which is sparingly soluble in water. The formation of calcium fluoride is undesirable since it reduces the amount of free fluoride anions available for use in the remineralization process. Thus, it is desirable to provide a remineralizing product wherein the solution used to treat the teeth contains sufficient levels of dissolved fluoride anions to enhance the remineralization of the subsurface lesions.
Although the remineralization products disclosed in the aforementioned copending, commonly assigned patent applications are stable, it is continually desirable to provide alternative products which minimize the risk of premature precipitation of the cations and anions, particularly of the fluoride anions.
Accordingly, a primary object of this invention is to provide products and methods for the remineralization and the prevention of demineralization of human teeth, wherein the products and methods are capable of effectively incorporating calcium ions, phosphate ions and, if present, fluoride ions into the subsurface of a tooth.
A further object of this invention is to provide products and methods for the remineralization and the prevention of demineralization of human teeth, wherein the precipitation of the calcium, phosphate and, if present, fluoride ions is substantially avoided prior to diffusion of the ions into the subsurface of the tooth without reducing the rate of remineralization at the subsurface of the tooth.
Another object of this invention is to provide products and methods for the remineralization and the prevention of demineralization of human teeth, which do not require excessive amounts of solution or inordinately long or frequent exposure times.
Still another object of the present invention is to provide products for the remineralization and the prevention of demineralization of human teeth, wherein the products are easily usable by the consumer and do not differ significantly, in flavor or appearance, from customary dental cosmetics.
Yet another object of this invention is to provide an improved product and a method of preparing such product, wherein the product is maintainable in a single container, substrate or matrix and is capable of remineralizing lesions in the teeth and mineralizing normal teeth to prevent cariogenic lesions from forming therein.
A further object of this invention is to provide remineralizing/mineralizing products and methods which can directly form hydroxyapatite in the subsurface of a tooth subsurface without first forming an amorphous calcium phosphate as an intermediate.
Yet another object of the present invention is to provide products having the characteristics set forth in the foregoing objects and which are in the form of a chewing gum, a lozenge, candy, food product, tablet, powder, dragee, bon bon and the like.
A further object of the present invention is to provide remineralization/mineralization methods using products having the characteristics set forth in the preceding objects.
These and other objects which are achieved according to the present invention can be readily discerned from the following description.
The present invention provides effective remineralizing/mineralizing solid products and methods of using same which overcome the aforementioned problems and achieve the foregoing objects.
Specifically, the present invention provides solid products for remineralizing subsurface lesions and/or mineralizing exposed dentin tubules in teeth, containing:
(a) a cationic component containing at least one partially water-soluble calcium salt;
(b) an anionic component containing at least one water-soluble phosphate salt; and
(c) a separating component for separating components (a) and (b) in the product; the product being capable of releasing, preferably simultaneously, components (a) and (b) into water and/or saliva when the product is mixed with the water and/or saliva;
wherein components (a) and (b) have a pH in water such that a mixed aqueous composition formed by mixing components (a) and (b) with water and/or saliva has a pH of from about 4.0 to about 10.0;
further wherein the cationic component contains an amount of the calcium salt such that in the mixed aqueous composition a first portion of the calcium salt exists as dissolved calcium cations and a second portion of the calcium salt exists as undissolved calcium salt, the anionic component comprising an amount of the phosphate salt such that the mixed aqueous composition further contains dissolved phosphate anions released by the phosphate salt.
Remineralization and/or mineralization is effected by mixing (e.g., by chewing, sucking or eating) the above-described solid product with water and/or saliva such that the solid product releases components (a) and (b) in the water and/or saliva to form the mixed aqueous composition, and then applying the mixed aqueous composition to at least one surface of at least one tooth for a period of time sufficient to allow the dissolved calcium cations and the dissolved phosphate anions to diffuse through the surface of the tooth to the subsurface and/or dentin portion, wherein the diffused cations and anions precipitate to form an insoluble compound on the subsurface lesion and/or on the exposed dentin tubule, thereby remineralizing such lesion and/or mineralizing.such exposed tubule.
In the present invention, when the mixed aqueous composition is applied to the tooth (or teeth), the dissolved calcium cations and the dissolved phosphate anions in the aqueous composition do not immediately precipitate but rather diffuse through the surface of the tooth to the subsurface and/or dentin thereof, where the ions then precipitate to form an insoluble compound on the demineralized subsurface lesion(s) and/or on the exposed dentin tubule(s).
This invention is based on the discovery that such delayed precipitation of the calcium cations and the phosphate anions until such ions have diffused through the tooth surface to the subsurface and/or dentin can be achieved by using in the cationic component at least one calcium salt having partial water-solubility at a pH of from about 4.0 to about 10.0. With the use of the partially water-soluble calcium salt(s) in the cationic component of the products of this invention, the calcium cations and the phosphate anions in the mixed aqueous composition used to treat the tooth are able to remain soluble for the period of time sufficient to allow the cations and anions to diffuse through the surface of the tooth to the subsurface and/or dentin thereof, where, as stated above, the ions react to form an insoluble precipitate on the demineralized lesion(s) and/or exposed tubule(s).
An important advantage of using the partially water-soluble calcium salt(s) in the present invention is that at any point in time the low concentration of calcium cations does not insolubilize the phosphate anions which are needed for remineralization and/or mineralization. The undissolved calcium salt in the mixed aqueous composition will release additional calcium cations as dissolved calcium cations in the mixed aqueous composition are used up or swallowed during the remineralization and/or mineralization process. The dissolved calcium cations and the dissolved phosphate anions are able to remain soluble for a period of time sufficient to permit the cations and anions to diffuse through the tooth surface to the subsurface and/or dentin of the tooth before forming a precipitate. Instead of precipitating on the surface of the tooth, the calcium cations and the phosphate anions released by the products of this invention will form an insoluble precipitate on the demineralized lesion(s) in the tooth subsurface and/or on the exposed tubule(s) in the dentin portion of the tooth.
Another advantage resulting from the use of the partially water-soluble calcium salt(s) in the present invention is that high concentrations of the undissolved calcium salt can be added to the dentifrice formulation without the danger of excessive concentrations of calcium cations being released at any one time to the saliva.
A further advantage resulting from the use of the partially water-soluble calcium salt(s) in the present invention is that, as the calcium cations in the mixed aqueous composition are used up (i.e., precipitated), the undissolved calcium salt can release additional calcium cations to the composition so as to maintain the rate of the remineralization and/or mineralization process.
Thus, the use of the partially water-soluble calcium salt(s) in the present invention provides a practical way to ensure close to optimum levels of calcium cations throughout the remineralization and/or mineralization process.
The products of the present invention provide substantially improved remineralization and mineralization as compared with the prior art products discussed hereinabove.
In addition, the methods of the present invention overcome the disadvantages of the prior art methods discussed hereinabove in that the methods of this invention effect subsurface remineralization rather than surface remineralization. Since dental caries begins as a subsurface demineralization of the dental enamel, subsurface remineralization arrests and repairs the carious lesion before any permanent structural damage to the tooth occurs.
Furthermore, the methods of the present invention do not require preparation of the enamel surface, capping of the tooth, or removal of decay products.
In addition, consumers may conveniently practice the methods of the present invention without substantially changing their dental care habits.